Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to a novel 4,4-difluo-1,2,3,4-tetrahydro-5H-1-benzozepine derivative or a salt thereof useful as a medicament, particularly a therapeutic agent for central diabetes insipidus and nocturia.
• the present invention relates to a pharmaceutical comprising the compound as an active ingredient.
• Arginine vasopressin is a 9-amino acid peptide that is biosynthesized and secreted by the hypothalamus-pituitary system.
• AVP receptors are classified into three subtypes: V la , V lb and V 2.
• the main pharmacological actions of AVP in the periphery include vasoconstriction via V Ia receptors and V 2 receptors. Antidiuretic action is known.
• V 2 receptor selective agonist the peptide desmopressin (the cysteine amino group at position 1 of AVP was deleted and arginine at position 8 was converted into a form) was synthesized. It is used to treat diabetes insipidus (Non-patent Document 1).
• oral desmopressin has a very low bioavailability and requires high doses to be effective. For this reason, desmopressin preparations are expensive, and side effects are often observed due to variation in absorption among individuals. Therefore, the development of a non-peptide antidiuretic with high bioavailability that selectively stimulates the V 2 receptor is expected.
• Patent Document 5 a benzozepine derivative represented by general formula (E) (Patent Document 6) and a benzoheterocyclic compound represented by General Formula (F) or General Formula (G) (Patent Document 7, Patent Document 8) Patent Document 9) is known as a V 2 receptor selective agonist.
• Patent Document 10 Patent Document 11
• Patent Document 12 Patent Document 12
• Patent Document 10 and Patent Document 1 2 include benzoyl which is substituted at the 1-position of the benzozepine according to the present invention, and a 4-, 4-difluorine-substituted 1,4-, 3-substituted CF 3 or halogen at the 2-position.
• Patent Document 11 describes a heteroaryl group bonded to a carboel substituted at the 1-position of benzozepine.
• benzozepine according to the present invention is bonded to a ring bonded to a carbonyl substituted at the 1-position, such as -0-, -S-, -NH-, or -N (low grade alkyl) - 4,4 Jifunoreo port having a substituent containing a - 1,2,3,4-tetrahydro - 5 but do not disclose H-1-Benzoazepin derivatives.
• Patent Document 1 International Publication No. 99/06 4 09 Pamphlet
• Patent Document 2 Pamphlet of International Publication No. 99/06403
• Patent Document 3 International Publication No. 00/46224 Pamphlet
• Patent Document 5 International Publication No. 97/22591 Pamphlet
• Patent Document 6 Japanese Patent No. 2926335
• Patent Document 7 Japanese Patent No. 3215910
• Patent Document 8 Japanese Patent Application Publication No. 11-349570
• Patent Document 9 Japanese Patent Application Publication No. 2000-351768
• Patent Document 1 0] International Publication No. 9 5/06035 pamphlet
• Patent Document 1 Pamphlet of International Publication No. 98/39325
• Patent Literature 1 2 Japanese Patent Application Publication No. 9-221475. Disclosure of the Invention
• the present inventors conducted intensive research on a compound having a V 2 receptor agonistic action that can be expected to be effective against central diabetes insipidus and Z or nocturia, and found a novel 4,4-difluo-1, The present inventors have found that a 2,3,4-tetrahydro-5H-1-benzozepine derivative has an excellent effect and completed the present invention.
• the compound of the present invention Is compared with Benzoazepin derivatives having v 2 receptor agonism had inhibitory effect against drug bill Crane to enzyme CYP3A4 ⁇ Pi CYP2C9 has been found that very low.
• a novel 4,4-difluo mouth-1,2,3,4 represented by the following general formula (I) useful as a therapeutic agent for central diabetes insipidus and Z or nocturia -Tetrahydro-5H-1-benzazepine derivative or a pharmaceutically acceptable salt thereof; and a pharmaceutical comprising an active ingredient of the above or any of these compounds; in particular, the above-mentioned arginine pasopressin V 2 receptor agonist
• the above-mentioned medicament which is a therapeutic agent for night pollakiuria or a therapeutic agent for central diabetes insipidus is provided.
• R 1 optionally substituted amino, —OH, or —0-lower alkyl.
• R 2 CF 3 or halogen.
• R 3 H or halogen.
• a, b each represents a single bond or a double bond, one being a single bond and the other being a double bond.
• -X- each represents a single bond or a double bond, one being a single bond and the other being a double bond.
• -A- -0-, -S-, -NH-, or -N (lower alkyl)-.
• the compound of the present invention has a chemical structural feature in that it has a difluoro group at the ring carbon atom adjacent to the benzozepine ring carbon atom substituted by the substituted methylidene group, and the conventionally known V 2 receptor It is completely different in structure from a selective agonist. Since the compound of the present invention has a difluoro group, the double bond that cooperates with the carboel group is not isomerized and has sufficient stability in vivo.
• R 1 is preferably represented by the above general formula (I), which is a group represented by the formula (I 1), the formula (II 1), —OH, or —0-lower alkyl.
• the salts that are acceptable are preferred.
• R 11 -0H S -0-lower alkyl, -C0 2 H, -C0 2 -lower alkyl, and 1 or 2 Two lower alkyl, optionally substituted with a group selected from the group consisting of carbamoyl, lower alkyl, or -H.
• Z 2 A single bond or lower alkylene.
• R 15 -H, -OH, -O-lower alkyl, -C0 2 H, -C0 2 -lower alkyl, carpamoyl optionally substituted by one or two lower alkyls, optionally substituted Iaryl, optionally substituted cycloalkyl, optionally substituted aromatic heterocycle, or optionally substituted non-aromatic heterocycle.
• R 13 and R 14 non-aromatic cyclic amino group which may be substituted together with the adjacent nitrogen atom.
• R 1 is a group represented by the formula (II); & is a single bond; b is a double bond; -X-force -CH-CH-; -Y- is -CH-, a new 4,4-difluo- mouth-1 represented by the above general formula (I) 1 , 2,3,4-Tetrahydrin-5H-1-benzozepine derivative or a pharmaceutically acceptable salt thereof.
• R 3 is —H or —F, a novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzozepine derivative or its
• the pharmaceutically acceptable salts of are preferred.
• a particularly preferred compound is a compound selected from the group consisting of compound group P and compound group Q or a pharmaceutically acceptable salt thereof.
• a compound selected from compound group P or The pharmaceutically acceptable salt is preferred.
• the “compound group Q” is a group consisting of
• R 1 groups of formula (II) or the formula (III) are preferred; more preferably a group represented by the formula (II); Z 1 is a single bond, R 12 is - H and R 11 is optionally substituted lower alkyl, the above formula (I
• a group represented by I) is more preferred; Z 1 is a single bond, R 12 is —H, R 11 is substituted with one or more substituents selected from the group consisting of S—OH and carpamoyl
• R 2 is preferably trifluoromethyl or black mouth; trifluoromethyl is particularly preferable.
• R 3 is preferably —H or fluorite; particularly preferably —H or 7-fluoro.
• a is a single bond
• b is a double bond
• -X-force S-CH CH-and -Y-force S-CH- are preferable.
• -A- is preferably -0-.
• lower alkyl which may be substituted is preferable; lower alkyl which may be substituted with F is particularly preferable.
• lower alkyl means a monovalent group of a linear or branched carbon chain of C I-6 , specifically, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl, or Isopuropiru, Ri these structural isomers der such tert- butyl, preferably of C w alkyl methyl, Echiru, propyl, butyl, Isobuchi It is le.
• lower alkylene refers to a divalent group of straight or branched carbon chain, specifically, for example, methylene, ethylene, trimethylene, methylmethylene, main Chiruechiren, dimethylmethylene and the like fist I can get lost.
• “Lower alkenyl J” means a monovalent group of carbon chain having at least one double or straight chain of C 2-6 , specifically, for example, bulle, allyl, 1-butyl. These structural isomers such as phenyl, 2-butyl, 1-hexenyl or 3-hexenyl, or 2-methylallyl, preferably allyl, 2-methyl-1-propen-3-yl.
• lower alkynyl means a monovalent group of a carbon chain having at least one triple bond in a straight or branched 6, specifically, for example, Echuru, Puroparugi - le, 1-
• These are structural isomers such asoverlappingyl, 3-butyur, 1-hexyl or 3-hexyl, or 3-methyl small-ptynyl, and are preferably propargyl and 1-ptyn-4-yl.
• Cycloalkyl means a monovalent group of a C 3 _ 8 non-aromatic hydrocarbon ring which may partially have an unsaturated bond, specifically, for example, cyclopropyl, cyclo Pentinole, Cyclohexyl / Le, Cyclooctenole, Cyclohexenole, Cyclone Octanegel and the like. '
• Aryl means a monovalent group of a monocyclic to tricyclic C 6-14 aromatic hydrocarbon ring, and specifically includes, for example, fuer, naphthyl, etc., preferably phenyl. It is.
• “Aromatic heterocycle” means a monovalent group of an aromatic ring having a mono- to tricyclic hetero atom such as nitrogen, oxygen, sulfur, etc., specifically, for example, pyridyl, chael, Furyl, pyr Camill, pyridazinyl, thiazolyl, pyrimidinyl, virazolyl, pyrrolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl Etc., and preferably pyridyl.
• Non-aromatic heterocycle means a heterocycle such as nitrogen, oxygen, or sulfur which may have a partially unsaturated bond and may be condensed with azimuth or an aromatic heterocycle.
• a monovalent group of 5 to 7-membered ring having an atom specifically, for example, pyrrolidyl, imidazolidinyl, piperidyl, piperagel, azepinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydrochel, etc.
• Non-aromatic cyclic amino group means a 3- to 10-membered non-aromatic cyclic amine that may have a partially unsaturated bond and may contain nitrogen, oxygen, or sulfur, Preferably, it means a monovalent group of a 5- to 7-membered non-aromatic cyclic amine such as pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazil, virazolidinyl, dihydropyrrolyl. Among them, pyrrolidinyl, piperidinyl, piperazur, and morpholinyl are preferable.
• Halogen means a monovalent group of a halogen atom, and specific examples thereof include fluoro, black-out, promo, and iodine.
• the permissible substituent of the term “optionally substituted” may be any substituent that is usually used as a substituent of each group, and one per each group. You may have the above substituent.
• R 1 Specific examples of the “optionally substituted amino” in R 1 include groups represented by the general formulas (II) and (III).
• Optionally substituted cycloalkyl in B, “optionally substituted aryl”; R 12 , “optionally substituted aryl” in R 15 , “optionally substituted cyclo” Alkyl ”,“ optionally substituted aromatic heterocycle ”,“ optionally substituted non-aromatic heterocycle ”; and“ optionally substituted non-aromatic cyclic ”in R 13 and R M Substituents allowed in the “amino group”; Examples include groups represented by (a) to (h).
• R z is -OH, -0-lower alkyl, an amino optionally substituted with one or two lower alkyls, a force rubermoyl optionally substituted with one or two lower alkyls, an aryl A lower alkyl, which may be substituted with one or more groups selected from the group consisting of an aromatic heterocyclic ring and a neurogen;
• (E) -CHO, -CO-R z, -C0 2 H, -C0 2 -R z, 1 or 2 R z may be substituted by Karupamoiru, Shiano;
• lower alkyl which may be substituted or “substituted” in B
• substituent allowed in “good lower alkenyl” and “optionally substituted lower alkynyl” include the groups shown in the above (a) to (g).
• the compound of the present invention represented by the general formula (I) may contain an asymmetric carbon atom depending on the kind of the substituent, and optical isomers based on this may exist.
• the present invention includes all of these optical isomer mixtures and isolated ones.
• the compounds of the present invention may have tautomers, but the present invention includes a mixture of these isomers or a mixture thereof.
• the compound of the present invention may form a salt and is included in the present invention as long as the salt is a pharmaceutically acceptable salt.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid
• organic acids such as lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, P-toluenesulfonic acid, aspartic acid or glutamic acid, sodium, potassium, calcium, magnesium, etc.
• Examples include inorganic bases, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and ammonium salts.
• the present invention also includes various hydrates, solvates and crystalline polymorphs of the compound of the present invention and pharmaceutically acceptable salts thereof.
• the compounds of the present invention also include all compounds so-called prodrugs that are metabolized in vivo and converted to the compounds having the general formula (I) or salts thereof. Examples of the group that forms the prodrug of the present invention include those described in Prog. Med “5; 2157-2161, 1985., Yodogawa Shoten, 1990," Development of pharmaceutical products ", Chapter 7 Molecular design 163-198 Examples include groups described on the page.
• the compounds of the present invention and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent. You can.
• the typical production method is illustrated below.
• suitable protecting group include a hydroxyl group, a carboxyl group, and an amino group
• examples of their protecting groups include Greene and Utz (Wuts, “Proteetive Groups in Organic Synthesis (third edition). ) ”Can include the fell groups described in d, which may be used as appropriate depending on the reaction conditions.
• R 2 , a, b, X, ⁇ , and ⁇ represent the above meanings;
• Lv represents a leaving group;
• B 1 represents B or a protecting group for a hydroxyl group, an amino group, or a sulfanyl group.
• R a represents a force lpoxyl group, a lower alkyloxycarbonyl group or a cyano group, and so on.
• This production method is a method for producing a compound (d) by substituting the leaving group Lv of the compound (a) with the compound (b) to produce the compound (c), and hydrolyzing as necessary.
• Examples of the leaving group Lv in the compound (a) include fluoro, black mouth, methanesulfonyloxy, p.toluenesulfonyloxy, trifnoreo mouth methanesulfonylo. And chlorosulfonyl, preferably methanesulfonyloxy.
• the reaction can be carried out in the absence of solvent, or aromatic hydrocarbons such as benzene, toluene, xylene; etherols such as jetyl ether, tetrahydrofuran (THF), dioxane; dichloromethane, 1,2-dichloroethane, black mouth form, etc.
• Aromadom hydrocarbons such as benzene, toluene, xylene
• etherols such as jetyl ether, tetrahydrofuran (THF), dioxane; dichloromethane, 1,2-dichloroethane, black mouth form, etc.
• Halogenated hydrocarbons ⁇ , ⁇ -dimethylformamide (DMF); dimethylacetamide (DMA); N-methylpyrrolidone; dimethylsulfoxide (DMSO); esters such as ethyl acetate (EtOAc); Inert solvent such as acetonitrile, or methanol
• an organic base preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine
• a metal salt base preferably carbonated potassium, carbonate Cesium, sodium hydroxide, sodium hydride
• Reaction is inactive in the reaction to compound (c), such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohol solvents, DMF, DMA, DMSO, pyridine, water, etc.
• Cooling in the presence of mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid, organic acids such as formic acid and acetic acid, or bases such as sodium hydroxide, lithium hydroxide, carbonated lithium, sodium carbonate, cesium carbonate or ammonia It can be carried out under reflux or heating.
• the reaction temperature can be appropriately selected depending on the compound. Gu Daiichi Manufacturing Method>
• This production method is a compound produced by the above intermediate production method (compound condensed with compound (la>) (lb) is produced and hydrolyzed to produce compound (lc), and by condensing compound (Id), compound (I) of the present invention wherein B 1 is B or B 1 is a hydroxyl group, This is a method for producing a compound (le) which is a protecting group for a mino group or a sulfanyl group.
• Compound (d) can be used as a free acid in the reaction, but its reactive derivative can also be used in the reaction.
• Compounds (the first reactive derivatives include ordinary esters such as methyl ester, ethyl ester, tert-butyl ester; acid chloride, Acid halides such as acid promides; acid azides; active esters with N-hydroxybenzotriazole, P-nitrophenol, N-hydroxysuccinimide, etc .; symmetrical acid anhydrides; alkyl halocarboxylic acids such as alkyl carbonate halides Mixed acid anhydrides such as esters, piperoyl halides, P-toluenesulfonic acid chlorides; phosphoric acid mixed acid anhydrides obtained by reacting diphenylphosphoryl chloride and N-methylmorpholine And mixed acid anhydrides.
• dicyclohexyl carpositimide DCC
• ⁇ ⁇ -canoleporobibis-1H-imidazole
• a condensing agent such as diphenylphosphoryl azide (DPPA), ditylphosphoryl cyanidya 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD).
• DPPA diphenylphosphoryl azide
• WSCD ditylphosphoryl cyanidya 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
• an acid chloride method a method of reacting in the presence of an active esterification agent and a condensing agent, and a method of subjecting a normal ester to an amine treatment can be conveniently and easily used as the compound of the present invention.
• the reaction varies depending on the reactive derivative and condensing agent used, but it is cooled in an organic solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF, DMSO, etc. Under cooling, at room temperature, or at room temperature to under heating.
• organic solvent inert such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF, DMSO, etc.
• the compound (la) is used in excess, or N-methylmorpholine, trimethylamine, triethylamine, disopropylethylamine, ⁇ , ⁇ -dimethylaniline, pyridine, 4- ( ⁇ , ⁇ - Reaction in the presence of a base such as (dimethylamino) pyridine, picoline, lutidine, etc. may be advantageous in order to facilitate the reaction.
• a salt composed of a weak base and a strong acid such as pyridine hydrochloride, pyridine ⁇ -toluenesulfonate, and ⁇ , ⁇ -dimethylaniline hydrochloride may be used.
• Pyridine can also be used as a solvent.
• the reaction is preferably carried out in the presence of a base such as pyridine, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylaniline, or a salt such as pyridine hydrochloride in a solvent such as acetonitrile or DMF.
• a base such as pyridine, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylaniline, or a salt such as pyridine hydrochloride in a solvent such as acetonitrile or DMF.
• the reaction can be carried out according to the second step of the intermediate production method.
• the reaction can be carried out according to the first step of the first production method.
• Compound (le) can be led to compound (I) of the present invention by removing a protecting group as necessary, or by introducing a necessary side chain according to a conventional method. Necessary side chains can be introduced according to the third step of the second production method described later.
• B 2 represents a protective group for a hydroxyl group, an amino group or a sulfanyl group. The same shall apply hereinafter.
• the reaction can be carried out according to the first step of the first production method.
• Examples of the protecting group for hydroxyl group, amino group or sulfanyl group include
• a method of removing benzyl group by acting pentamethylbenzene in a strongly acidic solution such as trifluoroacetic acid can be used.
• Examples of the leaving group Lv in the compound (2c) include black mouth, promo, odo, methanesulfo-oxy, p. P-toluene / rephonyloxy.
• a normal alkylation reaction can be used.
• compounds (2b) and (2c) are used in a solvent inert to the reaction such as acetonitrile, DMF, DMSO, ethers, etc.
• a solvent inert such as acetonitrile, DMF, DMSO, ethers, etc.
• Reactions using compound (2d) are not possible with ethers, DMF ⁇ N-methylpyrrolidone, etc. Can be carried out under Mitsunobu reaction conditions in the presence of an organic solvent such as triphenylphosphine, dialkyl azodicarboxylate such as diethylpropyl azodicarboxylate
• the reaction can be carried out according to the second step of the first production method.
• the reaction can be carried out according to the first step of the first production method.
• some of the compounds of the present invention represented by the formula (I) can be obtained from the compounds of the present invention obtained by the first production method or the second production method by known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis. It can be produced by arbitrarily combining processes that can be normally explored by those skilled in the art, such as decomposition. Specifically, for example, oxidation of sulfur atoms with oxidizing agents such as metabenzoic perbenzoic acid can be mentioned, and such reactions are known as “Experimental Chemistry Course 4th Edition” (Maruzen Co., Ltd., 1990-1992). It can be carried out by applying the method described in 1.
• these steps that can be usually employed by those skilled in the art are not limited to application to the compound of the present invention, and can also be applied to production intermediates. Specifically, for example, it can be applied to the compound obtained in the third step of the second production method, and then it can proceed to the next step.
• the compound of the present invention produced in this way is isolated or subjected to salt formation treatment by a conventional method as isolated and purified as a salt thereof.
• Isolation / purification is carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatographies.
• Various isomers can be isolated by conventional methods utilizing the difference in physicochemical properties between isomers. For example, a racemic mixture is obtained by a general racemate resolution method such as a method of optical resolution by diastereomer salt with a general optically active acid such as tartaric acid. Can lead to optically pure isomers. Further, the diastereomeric mixture can be separated by, for example, fractional crystallization or various chromatography. Optically active compounds can also be produced by using appropriate optically active raw materials. Industrial applicability
• the compound of the present invention has an excellent action on the arginine vasopressin V 2 receptor. Therefore, the compound of the present invention has an antidiuretic action with a profile based on this action, and is useful for urination disorder and large-scale urine. It is effective for prevention and / or treatment. In addition to these, it has a blood coagulation factor VIII and von Willebrand factor release action based on the action of the V 2 receptor, useful for various bleeding states, spontaneous bleeding, hemophilia Von Willebrand disease, uremia, congenital or acquired platelet dysfunction, traumatic and bleeding during surgery, cirrhosis, etc.
• the compounds of the present invention for inhibitory activity against drug-metabolizing enzymes CYP3A4 and CYP2C9 is very small, concerns drug interactions to other drugs metabolized via CYP3A4 or CYP2C9 is known conventionally alginate - Npasopureshin V 2 Compared to benzazepine derivatives that have receptor agonistic activity, it is superior in that it can be used safely in combination therapy with other drugs.
• the drugs metabolized by CYP3A4 include sympastatin, oral pastatin, flupastatin, midazolam, diphedipine, amlodipine, and -cardipine.
• the drugs metabolized by CYP2C9 include diclofenac, ibuprofen, Glibenclamide, oral sultan, etc. (General Clinical, 48 (6), 1427-1431, 1999.).
• Inhibition rate (%) 1 0 0-(d-B / (Co-Bi) X 1 0 0
• d Amount of [ 3 H] -pasopressin bound to the membrane specimen when the test compound and [ 3 H] -pasopressin co-exist with a known concentration for treatment with the receptor membrane specimen.
• the concentration (IC 50 value) of the test compound at which the inhibition rate was 50% was calculated from the above formula, and the affinity of the test compound for the receptor, that is, the dissociation constant (Ki) was calculated from the following formula.
• Dissociation constant (Ki) IC 50 / (1 + [L] / Kd)
• Kd Pasopressin receptor dissociation constant determined from saturation binding experiments (table 1 )
• the comparative compound is a compound of Example 32 described in International Publication No. WO 97/22591 (Compound name: 2-[(5R) small (2-Kokuguchi-4-pyrrolidine-1-ylbenzoinole)) -2,3,4,5-tetrahydrobenzazepine-5-yl] -N-isopropylacetamide).
• test compound In the experiment, Wistar male rats (10 to ⁇ 2 weeks old) were used. The test compound was orally administered, and 15 minutes later, 30 ml / kg of distilled water was forcibly orally administered (water load). Urine up to 4 hours after water load was collected in a metabolic cage, and the urine output when the water load was 100% was calculated as the urinary excretion rate. In the evaluation, the dose of test compound (ED 5G ) required to reduce the urinary excretion rate by 50% was used. As a result, it was clarified that the compound of the present invention has an excellent antidiuretic effect not only by intravenous administration but also by oral administration.
• the fluorescence intensity (excitation wavelength: 409 nm, fluorescence wavelength: 530 nm) was measured with a fluorescence plate reader.
• the inhibition rate was calculated using the same formula as in (4) above, and the concentration of the test compound at which the inhibition rate was 50%. (IC 50 ) was obtained and the results are shown in Table 3. (Table 3)
• the compounds of the present invention showed a very low inhibitory action on the drugs CYP3A4 and CYP2C9.
• the comparative compound is the same as the comparative compound shown in Table 1.
• the medicament of the present invention is usually used by using one or more of the compounds of the present invention represented by the general formula (I) and a simple substance for pharmaceutical use, excipients, and 13 additional agents usually used for formulation.
• Administration is any of oral administration via tablets, pills, capsules, granules, powders, liquids, injections such as intravenous injections, intramuscular injections, or parenteral administration via suppositories, nasal, transmucosal, transdermal, etc. It may be a form.
• the solid composition for oral administration according to the present invention tablets, powders, granules and the like are used.
• one or more active substances may contain at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybylpyrrole. It is mixed with don, magnesium aluminate metasilicate, etc.
• the composition is prepared according to conventional methods, with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, stabilizers such as lactose, Contains dissolution aids such as glutamic acid or aspartic acid May be.
• the glaze or pill may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a gastric or enteric film, if necessary.
• Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. Contains ethanol. In addition to the inert diluent, this composition may contain humectants, adjuvants such as suspending agents, sweeteners, flavors, fragrances, preservatives, 0
• Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• aqueous solution and suspension include distilled water for injection and physiological saline.
• non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as EtOH, and polysorbate 80.
• Such compositions further contain preservatives, wetting agents, emulsifiers, dispersants, stabilizers such as lactose, for example, solubilizing agents such as glutamic acid aspartic acid, and the like. May be.
• the daily dose is about 0.0001 to 50 mg / kg per body weight, preferably about 0.001 to 10 mg / kg, more preferably 0.01 to 1 mg / kg. This should be administered once or in 2 to 4 divided doses.
• the daily dose is about 0.0001 to 1 mg / kg per body weight, preferably about 0.0001 to 0.1 mg / kg, and is administered once or multiple times a day. The dose is appropriately determined according to the individual case in consideration of symptoms, age, sex, etc. However, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient.
• a 60% sodium hydrogenated oil dispersion (5.2 g) was suspended in 50 ml of DMF, and 6.73 ml of benzyl alcohol was added under ice cooling. After raising the temperature to room temperature, 12.3 g of 4-fluoro-2-trifluoromethylbenzoic acid was added, and the mixture was stirred at room temperature for 6 hours. A 1M aqueous hydrochloric acid solution was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 16.39 g of 4- (benzyloxy) -2- (trifluoromethylenole) benzoic acid.
• R A , B a substituent in the general formula
• nPr normal propyl
• cPr cyclopropyl
• complex data may be given depending on the presence of two or more conformers depending on the compound. Of these, only the peaks corresponding to the conformers considered to be mainly present are listed. Also these pea By measuring under heating, the peak converged to a peak indicating one kind of compound. (Table 4)
• Methyl 4-fluoro-2-2-trifluoromethylbenzoate 4.44 g was dissolved in 40 ml of DMF, 3.32 g of potassium carbonate and 4.10 ml of N-methylpropylamine were added, and the mixture was stirred at 80 ° C. for 14 hours. After cooling the reaction solution, water and EtOAc were added to carry out a liquid separation operation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off.
• Me Mechinole.
• Reference Example 1 1.09 g of compound 4 is dissolved in 10 ml of DMF, HOBt 324 mg, WSCD 460 mg, dimethylolamine (2.0 M THF solution) 1,20 ml and triethylamine 0.335 ml And then stirred at room temperature for 6 hours.
• Reference Example 2 Add 5M aqueous sodium hydroxide solution to the MeOH solution of the compound of 8 90. The mixture was stirred at C for 2.5 hours to obtain 4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoic acid.
• Methyl 4- ⁇ [(2S) -2-fluoropropyl] oxy ⁇ -2-trifluoromethyl) benzoate was prepared using the compound of Reference Example 36 as in Reference Example 32.
• Examples 2 to 16 shown in Table 10 were produced using the corresponding raw materials.
• Example 18 shown in Table 10 was produced using the corresponding raw materials. Further, in the same manner as in Reference Example 12, Examples 19 to 20 shown in Table 10 were produced using the corresponding raw materials.
• Example 22 shown in Table 10 was produced using the corresponding raw materials.
• Examples 1 2 to 1 to 7 shown in Tables 1 to 1 to 8 using the corresponding raw materials respectively, the methods described in the above production methods and examples, and methods obvious to those skilled in the art Or by these modified methods.
• Et Ethyl, nBu: Normalptyl, Ph: Phenyl, Py: Pyridyl, Bn: Benzyl, Gly: Carpamoylmethylamino (-NHCH 2 CONH 2 ), Etha: 2-hydroxyethylamino (-NHCH 2 CH 2 OH), Car: Amino (-NH 2).
• the number before the substituent indicates the substitution position. Specifically, for example, -NHPh (2-OH) represents 2-hydroxyphenylamino, and -NHCH2-Py) represents pyridine-2-ylmethylamino.
• Tables 20 to 36 below show the structures of other compounds of the present invention. These have been synthesized or can be synthesized by using the above-mentioned production methods, the methods described in the Examples, methods obvious to those skilled in the art, or variations thereof.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Diabetes (AREA)
• Urology & Nephrology (AREA)
• Hematology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (14)

Applications Claiming Priority (4)

Related Child Applications (2)

Publications (1)

Family

ID=33422056

Family Applications (1)

Country Status (17)

Cited By (2)

Families Citing this family (7)

Citations (4)

Family Cites Families (12)

• 2004
  • 2004-04-26 AT AT04729502T patent/ATE512951T1/de active
  • 2004-04-26 PL PL04729502T patent/PL1619185T3/pl unknown
  • 2004-04-26 PT PT04729502T patent/PT1619185E/pt unknown
  • 2004-04-26 WO PCT/JP2004/005998 patent/WO2004096775A1/ja not_active Application Discontinuation
  • 2004-04-26 RU RU2005136863/04A patent/RU2326868C2/ru not_active IP Right Cessation
  • 2004-04-26 EP EP04729502A patent/EP1619185B1/en not_active Expired - Lifetime
  • 2004-04-26 SI SI200431724T patent/SI1619185T1/sl unknown
  • 2004-04-26 NZ NZ542815A patent/NZ542815A/en not_active IP Right Cessation
  • 2004-04-26 KR KR1020057020359A patent/KR100882154B1/ko active IP Right Grant
  • 2004-04-26 DK DK04729502.7T patent/DK1619185T3/da active
  • 2004-04-26 CA CA2521492A patent/CA2521492C/en not_active Expired - Fee Related
  • 2004-04-26 AU AU2004234258A patent/AU2004234258B2/en not_active Ceased
  • 2004-04-26 MX MXPA05011521A patent/MXPA05011521A/es active IP Right Grant
  • 2004-04-26 BR BRPI0409718-1A patent/BRPI0409718A/pt not_active IP Right Cessation
  • 2004-04-26 US US10/554,150 patent/US7183271B2/en not_active Expired - Lifetime
• 2005
  • 2005-10-10 IL IL171332A patent/IL171332A/en active IP Right Grant
  • 2005-11-25 NO NO20055602A patent/NO333505B1/no not_active IP Right Cessation
• 2006
  • 2006-11-14 US US11/598,732 patent/US7807664B2/en active Active

Patent Citations (4)

Also Published As

Similar Documents

Legal Events